rs55689103

Positions:

chr7-103593755-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_005045.4(RELN):c.3839G>A(p.Gly1280Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0146 in 1,613,988 control chromosomes in the GnomAD database, including 217 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.011 ( 13 hom., cov: 33)

Exomes 𝑓: 0.015 ( 204 hom. )

Consequence

RELN
NM_005045.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 7.57

Variant links:

Genes affected

RELN (HGNC:9957): (reelin) This gene encodes a large secreted extracellular matrix protein thought to control cell-cell interactions critical for cell positioning and neuronal migration during brain development. This protein may be involved in schizophrenia, autism, bipolar disorder, major depression and in migration defects associated with temporal lobe epilepsy. Mutations of this gene are associated with autosomal recessive lissencephaly with cerebellar hypoplasia. Two transcript variants encoding distinct isoforms have been identified for this gene. Other transcript variants have been described but their full length nature has not been determined. [provided by RefSeq, Jul 2008]

RELN links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010104984).

BP6

Variant 7-103593755-C-T is Benign according to our data. Variant chr7-103593755-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 95219.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-103593755-C-T is described in Lovd as [Likely_benign]. Variant chr7-103593755-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0114 (1738/152274) while in subpopulation AMR AF= 0.0214 (328/15298). AF 95% confidence interval is 0.0195. There are 13 homozygotes in gnomad4. There are 836 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 13 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RELN	NM_005045.4 link	c.3839G>A	p.Gly1280Glu	missense_variant	27/65	ENST00000428762.6	NP_005036.2	P78509-1
RELN	NM_173054.3 link	c.3839G>A	p.Gly1280Glu	missense_variant	27/64		NP_774959.1	P78509-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RELN	ENST00000428762.6 link	c.3839G>A	p.Gly1280Glu	missense_variant	27/65	5	NM_005045.4	ENSP00000392423.1		P78509-1

Frequencies

GnomAD3 genomes

AF:

0.0114

AC:

1738

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00328

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0215

Gnomad ASJ

AF:

0.0164

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00103

Gnomad FIN

AF:

0.00264

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0168

Gnomad OTH

AF:

0.0163

GnomAD3 exomes

AF:

0.0102

AC:

2563

AN:

251166

Hom.:

AF XY:

0.0102

AC XY:

1380

AN XY:

135744

show subpopulations

Gnomad AFR exome

AF:

0.00246

Gnomad AMR exome

AF:

0.00966

Gnomad ASJ exome

AF:

0.0166

Gnomad EAS exome

AF:

0.0000545

Gnomad SAS exome

AF:

0.00101

Gnomad FIN exome

AF:

0.00333

Gnomad NFE exome

AF:

0.0161

Gnomad OTH exome

AF:

0.0145

GnomAD4 exome

AF:

0.0149

AC:

21802

AN:

1461714

Hom.:

204

Cov.:

AF XY:

0.0144

AC XY:

10479

AN XY:

727154

show subpopulations

Gnomad4 AFR exome

AF:

0.00251

Gnomad4 AMR exome

AF:

0.0105

Gnomad4 ASJ exome

AF:

0.0165

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000835

Gnomad4 FIN exome

AF:

0.00354

Gnomad4 NFE exome

AF:

0.0176

Gnomad4 OTH exome

AF:

0.0151

GnomAD4 genome

AF:

0.0114

AC:

1738

AN:

152274

Hom.:

Cov.:

AF XY:

0.0112

AC XY:

836

AN XY:

74450

show subpopulations

Gnomad4 AFR

AF:

0.00327

Gnomad4 AMR

AF:

0.0214

Gnomad4 ASJ

AF:

0.0164

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.00264

Gnomad4 NFE

AF:

0.0168

Gnomad4 OTH

AF:

0.0161

Alfa

AF:

0.0147

Hom.:

Bravo

AF:

0.0118

TwinsUK

AF:

0.0154

AC:

ALSPAC

AF:

0.0145

AC:

ESP6500AA

AF:

0.00227

AC:

ESP6500EA

AF:

0.0155

AC:

133

ExAC

AF:

0.0102

AC:

1238

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.0166

EpiControl

AF:

0.0183

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 25, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 21, 2013	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided

Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 11, 2017	- -

Norman-Roberts syndrome;C4225327:Familial temporal lobe epilepsy 7

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Norman-Roberts syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.71

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.32

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.14

T;.;.

Eigen

Pathogenic

0.86

Eigen_PC

Pathogenic

0.87

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.95

D;D;D

MetaRNN

Benign

0.010

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.3

M;M;.

PrimateAI

Uncertain

0.79

PROVEAN

Benign

-2.0

N;N;N

REVEL

Uncertain

0.34

Sift

Uncertain

0.014

D;D;D

Sift4G

Uncertain

0.010

D;D;D

Polyphen

1.0

D;D;.

Vest4

0.97

MPC

0.77

ClinPred

0.013

GERP RS

6.1

Varity_R

0.31

gMVP

0.88

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over